A high-throughput multi-microfluidic crystal generator (MMicroCryGen) platform for facile screening of polymorphism and crystal morphology for pharmaceutical compounds

Abstract

In this work, a novel multi-microfluidic crystallization platform called MMicroCryGen is presented, offering a facile methodology for generating individual crystals for fast and easy screening of the polymorphism and crystal habit of solid compounds. The MMicroCryGen device is capable of performing 8 × 10 cooling crystallization experiments in parallel using 8 disposable microcapillary film strips, each requiring less than 25 μL of solution. Compared to traditional microfluidic systems, the MMicroCryGen platform does not require complex fluid handling; it can be directly integrated with a 96-well microplate and it can also work in a “dipstick” mode. The produced crystals can be safely and directly observed inside the capillaries by optical and spectroscopic techniques. The platform was validated by performing a number of independent experimental runs for: (1) polymorph and hydrate screening of ortho-aminobenzoic acid, succinic acid and piroxicam; (2) co-crystal form screening of the p-toluenesulfonamide/triphenylphosphine oxide system; (3) studying the effect of o-toluic acid on ortho-aminobenzoic cooling crystallization (effect of structurally related additives). In all three cases, all known solid forms were identified with a single experiment using ∼200 μL of solvent and just a few micrograms of the solid material. The MMicroCryGen is simple to use, inexpensive and it provides increased flexibility compared to traditional crystallization techniques, being an effective new microfluidic solution for solid form screening in pharmaceutical, fine chemicals, food and agrochemical industries.